Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial

Clin Oncol (R Coll Radiol). 2015 Mar;27(3):168-75. doi: 10.1016/j.clon.2014.11.024. Epub 2014 Dec 16.

Abstract

Aims: To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma.

Materials and methods: The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables.

Results: HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m(2)) was 32.2 ± 0.9 μg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear-linear relationship between area under the concentration-time curve (AUC; mean 191 ± 6 μg·h/ml) and administered dose, especially when expressed as g/m(2). The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients.

Conclusion: The study supports the current nimorazole dose scheduling in patients.

Keywords: Head and neck carcinoma; hypoxic radiosensitisation; nimorazole; pharmacokinetics; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / blood
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism*
  • Female
  • Head and Neck Neoplasms / blood
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Nimorazole / administration & dosage
  • Nimorazole / adverse effects
  • Nimorazole / blood
  • Nimorazole / pharmacokinetics*
  • Radiation-Sensitizing Agents / administration & dosage
  • Radiation-Sensitizing Agents / adverse effects
  • Radiation-Sensitizing Agents / pharmacokinetics*
  • Randomized Controlled Trials as Topic
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • Radiation-Sensitizing Agents
  • Nimorazole